A continous supply of oxygen is essential to sustain life. Therefore, it is not surprising that the body has developed elaborate mechanisms for defense against hypoxia. Study of these hypoxic defense mechanisms constitutes the underlying theme of this Program Project. Six investigators will examine in animals and man, physiologic and pathologic responses to acute and chronic hypoxia in terms of control of ventilation and control of pulmonary hemodynamics and the lung microcirculation. The roles of hypoxic and hypercapnic ventilatory drives in controlling breathing in respiratory failure, during sleep, and during exercise, will be investigated. Histamine, prostaglandins, perivascular mast cells, and the direct effect of hypoxia will be examined in terms of pulmonary vascular control. Factors causing pulmonary capillary recruitment as a means of enhancing gas exchange will be studied. All of these mechanisms will be related to adaption and maladaptation to high altitude, including pregnancy, chronic mountain sickness, high altitude pulmonary edema, and oxygen transport. The basic aim is to discover how hypoxia and responses to it alter oxygen transport in terms of function of capillaries, vessels, organs, systems and intact animals and man in health and disease. The ultimate aim is to apply information gained to prevention and treatment of human disease. The approach in all sections is, first, to develop and validate the methods to be used, to apply these methods in vitro or in vivo animals studies to the questions asked, and finally, where possible, to investigate the questions in man. Hypoxia, i.e., restrictions on oxygen availability to the organism, is a fundamental aspect of may disease states and consequently these investigations have broad implications both to patients and to the millions of healthy individuals exposed to the hypoxia of high altitude.